Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu, China.
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education of China, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
J Alzheimers Dis. 2018;62(4):1737-1746. doi: 10.3233/JAD-171047.
Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain.
阿尔茨海默病（AD）患者大脑葡萄糖摄取/代谢受损被认为导致蛋白 O-GlcNAcylation 下调，通过tau 过度磷酸化促进 tau 发病。葡萄糖转运蛋白 3（GLUT3）是一种神经元特异性葡萄糖转运蛋白，其水平在 AD 脑中降低，这可能导致脑葡萄糖摄取/代谢受损。然而，导致 AD 脑中 GLUT3 减少的原因尚不完全清楚。在这里，我们报告 1）GLUT3 的减少与 AD 脑中蛋白 O-GlcNAcylation 的减少有关，2）GLUT3 水平与人类大脑中钙蛋白酶 I 激活呈负相关，3）钙蛋白酶 I 在体外裂解 GLUT3 的 N 端，以及 4）AD 脑中钙蛋白酶 I 的激活与蛋白 O-GlcNAcylation 呈负相关。此外，我们发现过表达 GLUT3 可增强 N2a 细胞中的蛋白 O-GlcNAcylation。钙蛋白酶 I 的过表达可抑制这些细胞中的蛋白 O-GlcNAcylation。这些发现表明，钙蛋白酶 I 过度激活导致 GLUT3 降解和 AD 脑中蛋白 O-GlcNAcylation 下调的新机制。
